To investigate the role of transglutaminase enzymes including human plasma Factor XIIIa in physiological processes such as blood clot stabilization, wound healing, cell proliferation, and skin formation, it is proposed that a series of compounds be synthesized and evaluated as selective, potent, active-site directed inhibitors of individual enzymes. Such inhibitors would also have potential application as therapeutic agents. The target compounds are synthetic peptides derived from alpha2-plasmin inhibitor or casein substrates and consisting of 10-15 amino acid residues in which the essential, active-site directed glutamine residues are replaced by residues that are glutamine analogs, derivatives, or antimetabolites. Selection of glutamine analogs is based on the results of inhibitor studies carried out in a model system with the enzyme: guinea pig liver transglutaminase that exhibits a broad specificity and acts on simple, protected amino acid and dipeptide substrates such as Benzyloxycarbonyl-L-glutamine (Z-Gln) and benzyloxycarbonyl-Lglutaminylglycine (Z-Gln-Gly). The initial synthesis of compounds as inhibitors is based on analogs of Z-Gln and Z-Gln-Gly in which Gln is replaced by: (1) an analog of glutamine with a side-chain thioamide; (2) methionine sulfoximine; (3) S-carbamyl cysteine; (4) homocysteine sulfonamide; (5) acivicin and (6) an analog of glutamine with a side-chain aldehyde. The initial evaluation is based on a fluoresence-HPLC assay in which the incorporation of monodanyslcadaverine into peptide substrates is determined. The most efficient replacements for glutamine will be incorporated into the larger peptides and evaluated. In related studies, peptide sequences on solid supports will then be tested as a substrates for the development of a standardized, solid-phase assay for Factor XIIIa.